This is an application for an ADAMHA Research Scientist (KO5) Award. The primary purpose of applying for an RSA is to reduce the applicant's teaching load to a level that will allow him to continue to pursue an active research career that focuses on identifying genetic factors that regulate nicotine tolerance and dependence. Because genetic factors apparently regulate individual differences in tobacco use, the applicant uses inbred or selectively bred mouse strains to identify behavioral and physiological responses to acute or chronic nicotine that show genetically-based variability, then uses these animals to test neurochemical hypotheses that attempt to explain individual differences. The research plan found in this application will provide an overview of the two major NIDA-funded. grants that support major aspects of the applicant's work. One of these grants (ROl DA-03194) is currently in its tenth year of continuous funding. This research effort has assessed the role of brain nicotinic receptors in regulating initial sensitivity and tolerance to nicotine, and led to the discovery that chronic nicotine treatment evokes a paradoxical up-regulation of brain nicotinic receptors, and tolerance to nicotine. When originally detected, we speculated that receptor up-regulation developed because of chronic agonist-induced desensitization or inactivation of the receptor and that this desensitization underlies tolerance. Progress to be recounted in this application will demonstrate that chronic nicotine treatment does, indeed, result in desensitized/inactivated receptors as measured by neurotransmitter release and ion flux as says and future experiments that build on these findings will be briefly described. The second major research effort is supported by a recently-funded Drug Abuse Research Center grant (P5O DA-05131). The applicant serves as scientific director of this grant as well as the PI of a component that is concerned with the regulation of sensitivity to nicotine and nicotinic receptor binding and function by glucocorticoid hormones. These studies are designed to provide an explanation for the often-made observation that smokers increase their use of tobacco when under stress. Our studies are building on our observation that glucocorticoid hormones modulate sensitivity to nicotine and modulate binding to brain nicotinic receptors. In addition to this research effort, the applicant will continue to train graduate students and postdoctoral fellows in the field of drug abuse, and will also continue to do some classroom teaching, albeit at a level less than the standard 2-3 course/year load.